Dendritic cells (DCs) have been (i) implicated, along with T cells, as one of the first leukocytes targeted by HIV after mucosal exposure and (ii) shown to transmit virus efficiently to CD4* T cells: direct transfer of captured/internalized virus (immature and mature DCs) and transfer of newly synthesized virus (immature DCs, iDCs). The SIV-macaque model is a precious tool to study the role of DCs in HIV transmission and disease progression. The DC-T cell milieu provides a distinctive niche in which SIV/HIV can propagate in vitro and in vivo, with different subsets of DCs and T cells influencing the level of virus growth. Wild type (wrt) vs ne/-defective {Anef) virus replication is dependent on the state of activation of the DC: wt overcomes the limitations of IDCs to foster infection in the DC-T cell milieu. In vivo Anef infection of macaques affords protection against wt infection, suggesting that in the absence of /7ef stronger effector immunity is mounted. In addition, HSV-2 infection augments HIV transmission possibly through the persistence of increased numbers of HIV target cells within the tissues and down-modulation of DC immunostimulatory capacity. But the exact mechanisms of such remain unclear. Within this new 5-year proposal we are expanding our current research to delve more deeply into this biology in order to define these early events in HIV transmission. This will be achieved through two new Specific Aims. Specifically, we hypothesize that HSV-2 enhances DCdriven HIV infection by initially increasing the numbers of highly susceptible a4/J7'^'^''CD4* T cells in the earliest stages of infection, as well as dampening overall effective immunity (reduced DC function, increased Tregs). Conversely, DC activation via poly(IC) (a synthetic analog of dsRNA) shuts down HIV/SIV replication. We believe that this might be due (at least in part) to the proper activation of DCs resulting in the triggering of important innate (e.g.. APOBEC) and adaptive responses that limit HIV/SIV spread. By studying wt and 4rtef infections we plan to delineate the role of iDCs and T cells (a4p7'^'^'^CD4'' T cells and Tregs) in mucosal transmission. We propose that the down-modulation of DC function by HSV-2 will enhance iDC-a4/J7'^'' T cell and IDC-Treg involvement even in Anef infection, while poly(lC) wilt limit HIV/SIV (and HSV-2) replication and augment anti-viral immunity (increased DC activation, fewer a4l3f'^'^CD4* T cells). Identifying the molecular requirements for virus transmission and the innate and adaptive responses that coincide with virus control will provide new targets for novel blocking strategies.